Abstract Certain members of the arenaviruses cause severe hemorrhagic fevers in humans and are classified as Category A agents. Of particular interest are the New World clade B viruses, whose members include the causative agents of Argentine, Brazilian, Venezuelan and Bolivian hemorrhagic fevers. These viruses are normally transmitted by contact with rodents, but can also be transmitted person-to-person. No licensed vaccines are available in the US and only limited therapeutic effect from the non-specific antiviral drug, ribavirin, has been described. Arenaviruses naturally infect both rodents and humans and display broad tissue tropism within their hosts. A major factor governing viral tropism is the nature of the cellular receptor, and interactions between viral glycoproteins and their receptor are important targets for antiviral agents. Previously, cc-dystroglycan has been identified as a receptor used by Lassa fever virus and certain other arenaviruses. However, our studies have determined that it is not a receptor used by the pathogenic clade B New World viruses. We here propose to identify the specific clade B receptor or receptors, investigate the basic biology and organization of the clade B glycoproteins, and apply this information to the development of therapeutic agents targeted to the entry stage of the arenavirus life cycle. Such approaches will complement drug development against other arenavirus targets and vaccine development.